title: Upregulation of postbacteremic TNF-alpha and IL-1alpha gene expression by alveolar hypoxia/reoxygenation in perfused rat lungs.
abstract: Decreases in the alveolar O2 tension commonly follow gram-negative bacteremic shock that progresses to the acute respiratory distress syndrome (ARDS). To examine the effects of alveolar hypoxia and reoxygenation (H/R) on postbacteremic pulmonary cytokine expression, lungs from Sprague-Dawley rats (n = 43) were perfused over 180 min after hematogenous infection with 10(9) live Escherichia coli serotype O55:B5 (EC) or infusion of 0.9% NaCl (NS). Compared with normoxic EC and NS controls, EC + H/R and NS + H/R lungs received 90 min of constant-flow hypoxia followed by 60 min of reoxygenation. Perfusates were cultured and analyzed for TNF-alpha, IL-1alpha, IL-1beta, and PGE2 while monitoring pulmonary artery pressure (Ppa). Changes in the filtration coefficient (Kf) were evaluated at 180 min when cytokine mRNA levels were assessed in lung homogenates. Transcripts of the anti-inflammatory cytokine TGF-beta1 and of inducible cyclooxygenase (COX-2) were similarly analyzed. For equivalent EC clearance, Ppa, and Kf as in normoxic EC, postbacteremic H/R increased TNF-alpha gene expression and doubled the export of TNF-alpha from the lungs, an effect not blocked by allopurinol. IL-1alpha transcripts were also increased in EC + H/R versus EC lungs, in contrast to the lack of change in IL-1beta, TGF-beta, or COX-2 mRNA levels, or in cell-associated or circulating IL-1beta and PGE2. Thus, gram-negative bacteremic lung infection and secondary alveolar H/R upregulate the expression of specific inflammatory cytokines compared with pulmonary infection under normoxic conditions, independently of xanthine oxidase-induced O2 radicals. These findings identify the alveolar PO2 as a potent immunomodulatory signal whose reductions early after gram-negative sepsis may enhance lung inflammation in ARDS.
authors.affiliation: Department of Internal Medicine, Saint Louis University School of Medicine, Missouri 63110-0250, USA. Matuscgm@wpogate.slu.edu
authors.forename: G M
authors.initials: GM
authors.lastname: Matuschak
authors.forename: C F
authors.initials: CF
authors.lastname: Munoz
authors.forename: C A
authors.initials: CA
authors.lastname: Johanns
authors.forename: R
authors.initials: R
authors.lastname: Rahman
authors.forename: A J
authors.initials: AJ
authors.lastname: Lechner
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000235:genetics*; D016207:Cytokines / Q000235:genetics*; D004927:Escherichia coli Infections / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D000860:Hypoxia / Q000235:genetics*; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000235:genetics; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008171:Lung Diseases / Q000235:genetics; D008297:Male; D010100:Oxygen / Q000494:pharmacology; D010477:Perfusion; D011650:Pulmonary Alveoli; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D010100:Oxygen